Pneumococcal Conjugate Vaccines: Epidemiology Guides Clinical Use

In 1990, a spectacular decrease of invasive Haemophilus influenzae type b (Hib) disease such as epiglottitis, purulent meningitis, and sepsis was observed in many countries including Germany. This decline occurred very shortly after licensure, introduction, and general recommendation of Hib conjugate vaccines for infants and young children [3]. The great Hib vaccination success was based on several facts:

Hib conjugate vaccines, combining the decisive antigen PRP (polyribo-sylribitol phosphate, a polysaccharide of the bacterial capsule) with a carrier protein, are able to induce a T-lymphocyte immune response which leads to priming of memory B-lymphocytes and induces a switch from short-lived IgM to persistent IgG antibody production. This immunological specificity is the basis for prolonged post-immunization immunity. Immunity induced by Hib conjugate vaccines not only protects the immunized individual from invasive disease (direct effect) but also effectively prevents Hib colonization of the nasopharynx and thereby reduces transmission of the organisms (indirect effect). Acceptance of Hib conjugate vaccine was extraordinarily high amongst health care providers and parents of young children (“anti-meningitis vaccine”). Hib vaccines were comparatively inexpensive and financial constraints were of low priority on the health care agenda at that time.

In this new epidemiological situation, Neisseria meningitidis and Streptococcus pneumoniae were suddenly left as the major causative agents of bacterial meningitis beyond the neonatal period in the western world. This and the proof of the concept of conjugate vaccines paved the way for the development of new meningococcal (group C to start with) and pneumococcal conjugate vaccines in the early 1990ies [1] [4].

The difficulty with pneumococcal vaccines, in contrast to Hib and meningococcal vaccines, is the great number of different antigenic serotypes circulating in populations and causing invasive disease. After successful completion of clinical trials [2] the first pneumococcal conjugate vaccine (PCV) was licensed in the European Union in 2000. It contained capsular polysaccharides of 7 prevalent serotypes conjugated to a carrier protein. At that time, these 7 serotypes were responsible for approximately 90% of all invasive pneumococcal diseases (IPD) in children under 2 years of age in the USA (where the vaccine was developed) and covered approximately 50–70% of all IPD in this age group in Europe including Germany [9]. In Germany, the way from licensure of PCV7 in 2000 to general recommendation in children under 2 years of age took a detour via an intermediate risk based recommendation (pre-term infants and others) which proved to be of little if any success [5] [10]. Finally, use of PCV7 was generally recommended for children under 2 years of age in 2006 and this proved to become a success story [5] [7]. In 2009, 2 new PCV with an expanded serotype coverage compared to PCV7 were licensed and introduced on the market in the European Union; they cover an additional 3 (PCV10) and 6 pneumococcal serotypes (PCV13, the successor of PCV7 from the same manufacturer), respectively.

In this issue of Klinische Pädiatrie, Rückinger and colleagues present epidemiological data from an ongoing nation-wide IPD surveillance programme which has accompanied the German national immunization programme ever since its introduction [8]. The authors are to be applauded for the outcomes of this remarkable and sustained collaboration between the national reference center for streptococcal infections in Aachen, epidemiologists at the Robert Koch-Institute in Berlin, and paediatric hospitals all over Germany which allows continuous evaluation of the development of IPD in children and adolescents. The investigators demonstrate that the remaining yearly burden of IPD due to serotypes covered by PCV7 in the period of July 2007 to June 2009 in children under 2 years of age was an estimated 31 cases – a significant decrease compared to the pre-vaccination era which can be explained by the successful prevention of vaccine serotype specific IPD. In comparison to PCV7 (31 cases), PCV10 now has the potential to prevent 68 cases and PCV13 to prevent 103 cases of the remaining 132 cases per year in this vulnerable paediatric age group.

In children 2–4 years old, for whom one dose of PCV13 (PCV 10 currently is not licensed beyond the second year of life) is now recommended if they belong to one of the specified medical high risk groups [6], the respective yearly preventable cases are 31 (PCV7), 74 (PCV10) and 94 (PCV13) of a total of 126. The extra benefit of the 23-valent conventional pneumococcal polysaccharide vaccine (PPV) when compared to PCV13 would only be 14 more preventable cases. However, this “benefit” is theoretical in nature as the effectiveness of PPV in preventing IPD in high risk children has not been proven. Therefore, PCV13 and not PPV is recommended to protect high risk children up to 5 years of age, i. e. within the limit of licensure of PCV13 in Germany today.

There are still several of open questions. With the use of PCV10 and PCV13, the epidemiology of IPD is expected to change again within a short or intermediate period of time. It will be interesting to see whether – and if so to which extent – immunizing a high proportion of children under 2 years of age will also have an indirect beneficial effect on IPD in other age groups such as older children and even adults, as it was the case with PCV7 due to the influence on bacterial transmission [2]. Further, duration of individual protection from IPD after complete immunization (number of doses depends on age at the first dose) is still unknown. Epidemiologic evidence from the use of PCV7 gives hope that protection is prolonged beyond the first 5–10 years after immunization and if natural boosters via nasopharyngeal colonisation continue to occur, it may even be longer. If these assumptions will proof to be true, the current recommendation of immunizing high risk children 2–4 years of age with PCV13 may become dispensable. Finally, and this is a theoretical caveat with any vaccine that does not protect independently of serotype, it remains to be seen whether wide-spread use of PCV10 and PCV13 will lead to an absolute increase of IPD by non-vaccine serotypes (“replacement”). Although this is possible if not likely to some extent, the overall benefit in the decrease of IPD by vaccine serotypes most probably will outweigh this theoretical concern and should not discourage us from widespread use of PCV10 and PCV13 today.

References

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• 2 Centers for Disease Control . Direct and indirect effects of routine vaccination of children with 7-valent pneumococccal conjugate vaccine and incidence of invasive pneumococcal disease United States 1998–2003.  MMWR. 2005;  54 893-897
• 3 Heininger U. Risiken von Infektionskrankheiten und der Nutzen von Impfungen [Complications of infectious diseases and benefits of immunization].  Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2004;  47 1129-1135
• 4 Lieberman JM, Chiu SS, Wong VK. et al . Safety and immunogenicity of a serogroups A/C Neisseria meningitidis oligosaccharide-protein conjugate vaccine in young children. A randomized controlled trial.  JAMA. 1996;  275 1499-1503
• 5 Robert Koch-Institut . Impfempfehlungen der Ständigen Impfkommission am Robert Koch-Institut/Stand Juli 2006; Begründung.  Epidem Bull. 2006;  31 255-260
• 6 Robert Koch-Institut . Impfempfehlungen der Ständigen Impfkommission am Robert Koch-Institut/Stand Juli 2010.  Epidem Bull. 2010;  31 279-298
• 7 Rückinger S, van der Linden M, Reinert RR. et al . Reduction in the incidence of invasive pneumococcal disease after general vaccination with 7-valent pneumococcal conjugate vaccine in Germany.  Vaccine. 2009;  27 4136-4141
• 8 Rückinger S, van der Linden M, Siedler A. et al . Potential benefits from currently available three pneumococcal vaccines for children.  Klin Padiatr. 2011;  223 61-64
• 9 von Kries R, Siedler A, Schmitt HJ. et al . Proportion of invasive pneumococcal infections in German children preventable by pneumococcal conjugate vaccines.  Clin Infect Dis. 2000;  31 482-487
• 10 Ziegler B, Strassburg HM. Vaccination status in very and extremely preterm infants at the age of 2 years – a nationwide pilot analysis.  Klin Padiatr. 2010;  222 243-247

Correspondence